Last update 19 Sep 2024

MGAT2

Last update 19 Sep 2024

Basic Info

Synonyms

alpha-1,6-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase, Beta-1,2-N-acetylglucosaminyltransferase II, GlcNAc-T II

+ [4]

Introduction

Plays an essential role in protein N-glycosylation. Catalyzes the transfer of N-acetylglucosamine (GlcNAc) onto the free terminal mannose moiety in the core structure of the nascent N-linked glycan chain, giving rise to the second branch in complex glycans.

Drugs associated with MGAT2

S-309309

Target

MGAT2

Mechanism

MGAT2 inhibitors

Active Org.

Shionogi, Inc.

Originator Org.

Shionogi & Co., Ltd.

Active Indication

Obesity

Inactive Indication-

Drug Highest PhasePhase 2

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

BMS-963272

Target

MGAT2

Mechanism

MGAT2 inhibitors

Active Org.

Bristol Myers Squibb Co.

Originator Org.

Bristol Myers Squibb Co.

Active Indication

Metabolic Diseases

Inactive Indication

Metabolic dysfunction-associated steatotic liver disease [+1]

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

JTP-103237

Target

MGAT2

Mechanism

MGAT2 inhibitors

Active Org.

Japan Tobacco, Inc.

Originator Org.

Japan Tobacco, Inc.

Active Indication

Obesity

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with MGAT2

NCT06106334 / CompletedPhase 1

A Crossover, Phase 1, Open-label, One-arm Study to Investigate the Effect of Itraconazole on the Pharmacokinetics of S-309309 in Healthy Male and Female Participants

The primary purpose of this study is to determine the effect of repeated administration of itraconazole on the pharmacokinetic (PK) profile of S-309309; and the PK of S-309309 following administration of S-309309 alone and co-administration with itraconazole

Start Date15 Nov 2023

Sponsor / Collaborator

Shionogi & Co., Ltd.

NCT05925114 / CompletedPhase 2

A Phase 2, Multicenter, Randomized, Double-blind, Dose-ranging, Placebo-controlled Study to Assess the Safety and Efficacy of S-309309 in Obese Adults

The primary objective of this study is to understand the efficacy of S-309309 on the body weight of obese adults.

Start Date21 Jun 2023

Sponsor / Collaborator

Shionogi, Inc.

NCT05247970 / CompletedPhase 1

A Phase 1 Randomized, Double-blind, Single and Multiple-dose Study to Assess the Safety, Tolerability, Pharmacokinetics, Food Effect, and Drug-Drug Interactions of S-309309 in Healthy and Obese Adult Study Participants

The primary aim of the study is to assess the safety and tolerability of S-309309 after oral administration in healthy adult or obese but otherwise healthy adult participants. The secondary aim of the study is to assess the pharmacokinetics of S-309309 and the effects on ECG parameters after oral administration in healthy or obese but otherwise healthy participants.

Start Date04 Jan 2022

Sponsor / Collaborator

Shionogi, Inc.

100 Clinical Results associated with MGAT2

100 Translational Medicine associated with MGAT2

0 Patents (Medical) associated with MGAT2

185

Literatures (Medical) associated with MGAT2

01 Nov 2024·Biochemical and Biophysical Research Communications

Subcellular imaging of MGAT1/MGAT2 homo- and heteromers in living cells using bioluminescence microscopy

Article

Author: Olczak, Mariusz ; Wiertelak, Wojciech ; Maszczak-Seneczko, Dorota

Protein-protein interactions (PPIs) play fundamental roles in many biological processes including the functioning of glycosylation machineries present in the endoplasmic reticulum (ER) and Golgi apparatus of mammalian cells. For the last couple of years, we have been successfully employing the most advanced version of the split luciferase complementation assay, termed NanoBiT, to demonstrate PPIs between solute carrier 35 (SLC35) family members with nucleotide sugar transporting activity and functionally related glycosyltransferases. NanoBiT has several unmatched advantages as compared with other strategies for studying PPIs. Firstly, the tendency of the free luciferase fragments to spontaneously associate is strongly reduced. As a consequence, the fragments of the reconstituted luciferase may dissociate upon the disruption of the PPI of interest. Secondly, the recombinant fusion proteins are expressed at low (near-endogenous) levels. Both of these features significantly minimize the possibility of obtaining false positive results. In this study we pushed the boundaries of this already powerful technique even further by coupling it with bioluminescence imaging of PPIs. Specifically, we visualized homo- and heterologous complexes formed by MGAT1 and MGAT2 glycosylation enzymes tagged with NanoBiT fragments and demonstrated ER-to-Golgi transitions between enzyme homo- and heteromers.

01 Jul 2024·Journal of Inherited Metabolic Disease

Deficient glycan extension and endoplasmic reticulum stresses in ALG3‐CDG

Article

Author: Freeze, Hudson H ; Alsharhan, Hind ; Edmondson, Andrew C ; Daniel, Earnest J P ; Lam, Christina ; Argon, Yair ; He, Miao

AbstractALG3‐CDG is a rare congenital disorder of glycosylation (CDG) with a clinical phenotype that includes neurological manifestations, transaminitis, and frequent infections. The ALG3 enzyme catalyzes the first step of endoplasmic reticulum (ER) luminal glycan extension by adding mannose from Dol‐P‐Man to Dol‐PP‐Man5GlcNAc2 (Man5) forming Dol‐PP‐Man6. Such glycan extension is the first and fastest cellular response to ER stress, which is deficient in ALG3‐CDG. In this study, we provide evidence that the unfolded protein response (UPR) and ER‐associated degradation activities are increased in ALG3‐CDG patient‐derived cultured skin fibroblasts and there is constitutive activation of UPR mediated by the IRE1‐α pathway. In addition, we show that N‐linked Man3‐4 glycans are increased in cellular glycoproteins and secreted plasma glycoproteins with hepatic or non‐hepatic origin. We found that like other CDGs such as ALG1‐ or PMM2‐CDG, in transferrin, the assembling intermediate Man5 in ALG3‐CDG, are likely further processed into a distinct glycan, NeuAc1Gal1GlcNAc1Man3GlcNAc2, probably by Golgi mannosidases and glycosyltransferases. We predict it to be a mono‐antennary glycan with the same molecular weight as the truncated glycan described in MGAT2‐CDG. In summary, this study elucidates multiple previously unrecognized biochemical consequences of the glycan extension deficiency in ALG3‐CDG which will have important implications in the pathogenesis of CDG.

01 Jun 2024·Carbohydrate Polymers

Enzymatic modular synthesis of asymmetrically branched human milk oligosaccharides

Article

Author: Li, Lei ; Ling, Peixue ; Chen, Congcong ; Li, Yi ; Fang, Junqiang ; Yang, Lin ; Li, Yinshuang ; Jiang, Qian ; Wang, Shuaishuai ; Guo, Yuxi

Human milk oligosaccharides (HMOs) are intricate glycans that promote healthy growth of infants and have been incorporated into infant formula as food additives. Despite their importance, the limited availability of asymmetrically branched HMOs hinders the exploration of their structure and function relationships. Herein, we report an enzymatic modular strategy for the efficient synthesis of these HMOs. The key branching enzyme for the assembly of branched HMOs, human β1,6-N-acetylglucosaminyltransferase 2 (GCNT2), was successfully expressed in Pichia pastoris for the first time. Then, it was integrated with six other bacterial glycosyltransferases to establish seven glycosylation modules. Each module comprises a one-pot multi-enzyme (OPME) system for in-situ generation of costly sugar nucleotide donors, combined with a glycosyltransferase for specific glycosylation. This approach enabled the synthesis of 31 branched HMOs and 13 linear HMOs in a stepwise manner with well-programmed synthetic routes. The binding details of these HMOs with related glycan-binding proteins were subsequently elucidated using glycan microarray assays to provide insights into their biological functions. This comprehensive collection of synthetic HMOs not only serves as standards for HMOs structure identification in complex biological samples but also significantly enhances the fields of HMOs glycomics, opening new avenues for biomedical applications.

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MGAT2

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